The present invention relates to novel tetrahydropyridine derivatives having substituted pyrrolidinone and oxime, which act on muscarinic acetylcholine receptors and thus useful as nootropics and therapeutic agents for neural diseases; and pharmaceutically acceptable salts thereof; processes for the preparation thereof; and pharmaceutical compositions comprising these compounds or salts.
Due to the increase in the number of the elderly population, the number of geriatric diseases such as dementia have increased dramatically. Senile dementia, as represented by Alzheimer""s disease, is a degenerative neural disease characterized by disorders of mental capacity including loss of memory, judgment and cognitive function. Patients suffering from Alzheimer""s disease show up to 90% degeneration of pre-synapse muscarinic acetylcholine neurons of the basal ganglia, which project into the frontal lobe and hippocampus, both of which manage learning, association, consolidation, and cognitive function such as perception in the cerebrum. However, the post-synapse muscarinic neurons in the forebrain and hippocampus are relatively unchanged. These facts suggest the strategy of medicinal development based on cholinergic deficiency hypothesis, which focuses on the stimulation of post-synapse receptors [See; R. T. Bartus, et al. Science, 217, 408-417 (1982)].
Tacrine is an acetylcholine esterase inhibitor that enhances available acetylcholine, which was developed as an agent involved in cognitive function. However, Tacrine had adverse effects. Recently, Aricept (donepezil, Eisai America, Inc., 1996), Exelon (rivastigmine, Novartis Pharmaceuticals Corporation, 2000) and Reminyl (galantamine hydrobromide, Janssen Research, 2001) having enhanced efficacy were developed [See; W. Greenlee, et al. I1 Farmaco, 2001, 56, 247-250]. However, oxotremorine, RS-86 and the like, which is a nonselective cholinergic agonist for directly stimulating cholinergic receptors, had adverse effects [See; R. Plate et al., Bioorg. Med. Chem., 2000, 8, 449-454].
Muscarinic choline receptors exist in the central and peripheral nervous systems in five subtype forms to play an important role in brain cognitive function. As the post-synapse muscarinic neurons in the forebrain and hippocampus are known to be relatively unchanged in patients suffering from Alzheimer""s disease, research in nootropics and therapeutic agents for Alzheimer""s disease, focus on developing muscarinic agonists selective for the central nervous system and M1 receptors to decrease adverse effects and increase the efficacy of a cholinergic drug.
Known muscarinic agonists active on the central nervous system include Talsaclidin (1997), YM-796 (1990), CI-1017 (2000), Xanomelin (1997), Milameline (1997), Sabcomeline (SB-202026, 1997), Alvameline (LU 25-109, 1997), AF-102 (1997), etc. [See; A. Fisher, Drug Dev. Res. 2000, 50, 291-297]. Additionally, drugs with pyrrolidine rings and active on the nervous system include agents to ameliorate conditions of Alzheimer""s disease such as oxotremorine compound [See; E. J. Trybulski et al., Bioorg. Med. Chem. Lett. 1992, 2, 827-832] and nootropics [See; D. Manetti et al., J. Med. Chem. 2000, 43, 1969-1974]. Although oxadiazole compounds of high affinity and excellent efficacy have been reported, they are known to have adverse effects. Recently, muscarinic agonists such as Pilocarpine (Salagen Tablets, MGI Pharma, Inc., 1998) and Cevimeline (AF102B, EVOXAC(trademark), SnowBrand Pharmaceuticals, Inc., 2000) were approved by FDA as therapeutic agents for xerostomia originating from studies on the Sjogren""s syndrome, a variety of autoimmune diseases affecting exocrine glands [See; Drugs of the future, 2000, 25(6), 558-562].
Muscarinic receptors are involved in psychosis, Alzheimer""s disease and Parkinson""s disease. Compounds that have activity on muscarinic acetylcholine receptors are useful for treatment of pain, glaucoma, schizophrenia, anxiety, manic-depressive psychosis (circular insanity), bipolar psychosis, depression, somnipathy, epilepsy, cerebral ischemia, fecal incontinence, gastrointestinal mobility and gastric secretion disorder [See; L. M. Merritt et al., U.S. Pat. No. 5,998,404].
Recently, the muscarinic receptor in post- and pre-synapse of the cholinergic nervous system, which is known to play an important role in learning and memory, was also found to regulate the process of forming amyloid precursor protein, which plays some role in precipitating beta-amyloid in patients suffering from Alzheimer""s disease. Further, muscarinic receptor agonist is known to accelerate secretion of soluble amyloid precursor protein and decrease phosphorylation of tau-protein. Accordingly, to develop nootropics and therapeutic agents for Alzheimer""s disease wherein beta-amyloid plaque and nerve fiber entanglement are accumulated, it is important to develop novel muscarinic receptor agonists with muscarinic acetylcholine receptor activity and high efficacy, low cholinergic adverse effects and selectivity for other receptors [See; C. C. Felder et al., J. Med. Chem. 2000, 43, 23, 4334-4353].
However, some compounds active on the muscarinic acetylcholine receptor have adverse effects such as hypersialosis, tearing and gastropathy. Accordingly, there is a need to develop novel compounds that have muscarinic acetylcholine receptor activity, selectivity for other receptors or subtypes, high efficacy and low cholinergic adverse effects.
The object of the present invention is to provide novel tetrahydropyridine derivatives having appropriately substituted pyrrolidinone and oxime, which show high efficacy, low cholinergic adverse effects and high affinity for muscarinic acetylcholine receptors; and pharmaceutically acceptable salts thereof; processes for the preparation thereof; and pharmaceutical compositions comprising these compounds or salts.
The present invention provides tetrahydropyridine derivatives of formula 1, 
wherein m is 0 or 1, n is 1 or 2, R1 is hydrogen, C1-4alkyl, C2-4 alkynyl or aryl, and R3 is C1-4 alkyl; and pharmaceutically acceptable salts thereof.
C1-4 alkyl as used herein represents a straight or branched alkyl group comprising 1 to 4 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and most preferably methyl.
C2-4 alkynyl as used herein represents a straight or branched hydrocarbon group having one triple bond and comprising 2 to 4 carbon atoms, such as ethynyl, propynyl (generally known as propargyl) butynyl, and most preferably propargyl.
Aryl as used herein represents phenyl, naphthyl or benzyl, and most preferably benzyl.
Most preferable are compounds of formula 1 according to the present invention wherein R1 is hydrogen, methyl, propargyl or benzyl and R3 is methyl.
Preferable compounds of formula 1 are
1-[3-benzyloxyimino-3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propyl]-pyrrolidin-2-one,
1-[2-benzyloxyimino-3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propyl]-pyrrolidin-2-one,
1-[3-methoxyimino-3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propyl]-pyrrolidin-2-one,
1-[2-methoxyimino-3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propyl]-pyrrolidin-2-one,
1-[3-hydroxyimino-3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propyl]-pyrrolidin-2-one,
1-[2-hydroxyimino-3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propyl]-pyrrolidin-2-one,
1-[3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-3-propyn-2-yloxyimino-propyl]-pyrrolidin-2-one,
1-[3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-2-propyn-2-yloxyimino-propyl]-pyrrolidin-2-one,
1-[2-hydroxyimino-2-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-ethyl]-pyrrolidin-2-one,
1-[2-methoxyimino-2-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-ethyl]-pyrrolidin-2-one,
1-[2-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-2-propyn-2-yloxyimino-ethyl]-pyrrolidin-2-one,
1-[2-benzyloxyimino-2-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-ethyl]-pyrrolidin-2-one, and
pharmaceutically acceptable salts thereof.
Pharmaceutically acceptable salts of compounds of formula 1 include acid addition salts. Acids for making pharmaceutically acceptable acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, sulfonic acid, fumaric acid, maleic acid, citric acid, lactic acid, tartaric acid, oxalic acid, or pharmaceutically acceptable organic and inorganic acid, and the like.
The present invention also provides a process for the preparation of tetrahydropyridine derivatives of formula 1, 
wherein m, n, R1 and R3 are as defined in the above, comprising:
i) performing a condensation reaction of a compound of formula 5, 
wherein m and n are as defined in the above, with R1ONH2.HCl, wherein R1 is as defined in the above, to obtain a compound of formula 8, 
wherein m, n and R1 are as defined in the above; and
ii) reacting the resulting compound of formula 8 with an alkyl iodide to form an alkyl pyridine salt, and then reducing the salt to obtain the compound of formula 1.
Below, a process for preparation of tetrahydropyridine derivatives of formula 1 of the present invention will be explained in more detail referring to Schemes 1 and 2. 
First, the compound of formula 5 is reacted with R1ONH2.HCl, such as benzyloxyamine hydrochloride salt, hydroxylamine hydrochloride salt, methyloxyamine hydrochloride salt and propargyloxyamine hydrochloride salt, in methanol/water(1.5:1) for about 12 hours. Subsequently, the reaction product is purified by separation with silica gel column chromatography to obtain the compound of formula 8.
The obtained compound of formula 8 is dissolved in acetone, and reacted with alkyl iodide for 4 hours at 0xc2x0 C. A small amount of diethyl ether is added and the mixture is filtered. After washing with acetone/diethyl ether and filtrating and drying, the pyridinium iodide salt of formula 9 is obtained. The salt compound is dissolved in ethanol/water (1:1), and reacted with sodium borohydride for 2 hours. Subsequently, the resulting product is purified by separation with silica gel column chromatography to obtain the compound of formula 1.
A compound of formula 5a, which is the compound of formula 5 wherein m is 0 and n is 1, can be synthesized in two ways as follows. 
First, as shown in Scheme 3, the compound of formula 5a 
can be obtained by alkylation of halogen at 3-position of a pyridine of formula 2, 
wherein X is iodine, bromine or chlorine, followed by a reaction with 2-(oxo-pyrrolidin-1-yl)-acetonitrile or 2-(oxo-pyrrolidin-1-yl)-acetic acid ethyl ester.
More specifically, after fully dissolving the compound of formula 2 in diethyl ether with stirring, a base such as n-butyl lithium is added dropwise for 30 minutes at xe2x88x9278xc2x0 C. After reacting for 30 minutes, 2-(oxo-pyrrolidin-1-yl)-acetonitrile or 2-(oxo-pyrrolidin-1-yl)-acetic acid ethyl ester are added dropwise for 30 minutes at xe2x88x9278xc2x0 C. After slowly increasing to room temperature, the reaction is preceded at room temperature for about 6 hours. Subsequently, the resulting product is purified by separation with silica gel column chromatography to obtain the compound of formula 5a. 
Second, as shown in Scheme 4, the compound of formula 5a can be synthesized by the coupling reaction of the compound of formula 2a 
wherein Xxe2x80x2 is B(OR)2, Bxe2x88x92(OR)3Li+ or SnBu3 and R is hydrogen or C1-4 alkyl, with 1-(2-bromoallyl)-pyrrolidin-2-one, followed by an ozonolysis.
More specifically, tributyltin, dimethylborate, or trimethylborate lithium salt of 3-pyridyl compound of formula 2a together with the solution of ditriphenylphosphine palladium dichloride and sodium carbonate are added to the solution of 1-(2-bromoallyl)-pyrrolidin-2-one, and the mixture is reacted for 15 minutes at room temperature and then heated at reflux for 18 hours. Subsequently, the resulting product is purified by separation with silica gel column chromatography to obtain the compound of formula 5a. 
Further, as shown in Scheme 5, the compounds of formula 5b and 5c, which are the compounds of formula 5 wherein m=0 and n=2, and m=1 and n=1, respectively, 
can be prepared by performing a coupling reaction with the compound of formula 6 
and the compound of formula 2, to obtain the alkyne compound of formula 7 
and then performing a hydration reaction to the alkyne compound of formula 7.
More specifically, the compound of formula 6 is reacted with the compound of formula 2 in dimethoxyethane/water (1:1) in the presence of a catalyst of tetrakis triphenylphosphine palladium, copper iodide and potassium carbonate to obtain the compound of formula 7. After isolating this compound of formula 7 and reacting with formic acid and mercury oxide, the resulting product is purified by separation with silica gel column chromatography. The former separated material is the compound of formula 5b while the latter one is the compound of formula 5c. 
Additionally, as shown in Scheme 6, the tetrahydro-pyridine compound of formula 11 can be prepared from the pyridine compound of formula 7 by the same preparation method as for the compound of formula 1.
Preferable compounds of formula 5 are 1-(3-oxo-3-pyridin-3-yl-propyl)-pyrrolidin-2-one, 1-(2-oxo-3-pyridin-3-yl-propyl)-pyrrolidin-2-one and 1-(2-oxo-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one.
Preferable compounds of formula 8 are
1-(3-benzyloxyimino-3-pyridin-3-yl-propyl)-pyrrolidin-2-one,
1-(2-benzyloxyimino-3-pyridin-3-yl-propyl)-pyrrolidin-2-one,
1-(3-methoxyimino-3-pyridin-3-yl-propyl)-pyrrolidin-2-one,
1-(2-methoxyimino-3-pyridin-3-yl-propyl)-pyrrolidin-2-one,
1-(3-hydroxyimino-3-pyridin-3-yl-propyl)-pyrrolidin-2-one,
1-(2-hydroxyimino-3-pyridin-3-yl-propyl)-pyrrolidin-2-one,
1-(3-propyn-2-yloxyimino-3-pyridin-3-yl-propyl)-pyrrolidin-2-one,
1-(2-propyn-2-yloxyimino-3-pyridin-3-yl-propyl)-pyrrolidin-2-one,
1-(2-hydroxyimino-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one,
1-(2-methoxyimino-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one,
1-(2-propyn-2-yloxyimino-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one,
1-(2-benzyloxyimino-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one, and
pharmaceutically acceptable salts thereof.
Preferable compounds of formula 11 are 1-[3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propyn-2-yl]-pyrrolidin-2-one and pharmaceutically acceptable salts thereof.
Free forms of compounds of formula 1 can be converted into acid addition salts by conventional methods such as addition of a solution containing appropriate acid in stoichiometric amounts. Pharmaceutically acceptable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, sulfonic acid, fumaric acid, maleic acid, citric acid, lactic acid, tartaric acid, oxalic acid, or pharmaceutically acceptable organic and inorganic acid, and the like.
Additionally, the present invention provides a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient together with a conventional carrier.
The compound of the present invention active on muscarinic acetylcholine receptor is useful for treating psychosis, Alzheimer""s disease, Parkinson""s disease, and the like. Further, they are useful for pain, glaucoma, schizophrenia, anxiety, manic-depressive psychosis (circular insanity), bipolar psychosis, depression, somnipathy, epilepsy, cerebral ischemia, sjogren""s syndrome, fecal incontinence, gastrointestinal mobility and gastric secretion disorder.
The pharmaceutical composition of the present invention can be administered orally or parenterally, such as intravenously or intramuscularly, in conventional manner.
The dosage depends on age, condition and weight of a patient, and the route of administration. The dosage amount of an active ingredient is typically about 0.01 to 200 mg per kg of body weight per day.
The compound of the present invention may be used as conventional solids or liquid formulations, for example in the form of non-coating or thin film-coating tablets, capsules, powders, granules or solutions. They are prepared with conventional methods, and active ingredient may be processed together with conventional pharmaceutical adjuvant, such as tablet binder, extender, preservative, tablet disintegrant, fluidity controller, plasticizer, wetting agent, dispensing agent, emulsifier, solvent, sustained releasing agent and/or antioxidant.
The following examples illustrate the invention in detail but one skilled in the art will appreciate that they are not intended to limit the scope of the invention.